Autosomal dominant tubulointerstitial kidney disease (ADTKD) in Ireland.

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of renal impairment resulting from mutations in the MUC1, UMOD, HNF1B, REN, and SEC61A1 genes. Neither the national or global prevalence of these diseases has been determined. We aimed to establish a database of patients with ADTKD in Ireland and report the clinical and genetic characteristics of these families. Methods: We identified patients via the Irish Kidney Gene Project and referral to the national renal genetics clinic in Beaumont Hospital who met the clinical criteria for ADTKD (chronic kidney disease, bland urinary sediment, and autosomal dominant inheritance). Eligible patients were then invited to undergo genetic testing by a variety of methods including panel-based testing, whole exome sequencing and, in five families who met the criteria for diagnosis of ADTKD but were negative for causal genetic mutations, we analyzed urinary cell smears for the presence of MUC1fs protein. Results: We studied 54 individuals from 16 families. We identified mutations in the MUC1 gene in three families, UMOD in five families, HNF1beta in two families, and the presence of abnormal MUC1 protein in urine smears in three families (one of which was previously known to carry the genetic mutation). We were unable to identify a mutation in 4 families (3 of whom also tested negative for urinary MUC1fs). Conclusions: There are 4443 people with ESRD in Ireland, 24 of whom are members of the cohort described herein. We observe that ADTKD represents at least 0.54% of Irish ESRD patients.

Metastatic Solitary Fibrous Tumour of the Kidney Presenting more than a Decade Later with Pulmonary Disease

Introduction Solitary fibrous tumours are rare mesenchymal tumours that most commonly originate from the visceral pleura. Extra-thoracic primary sites including; head and neck, soft tissue, retroperitoneum and the urological tract, are associated with late recurrence. Case We present a case of metastatic pulmonary Solitary Fibrous Tumour presenting 11 years post resection of renal primary Solitary Fibrous Tumour. The patient underwent apical segmentectomy of the right lower lobe extending to wedge excision of right upper lobe due to fissure involvement with lymphadenectomy. The patient was discharged day 12 post surgery. Discussion Robust guidance regarding long-term management of solitary fibrous tumours is lacking. Salvage resection offers favourable long-term prognosis. This case demonstrates the importance of long-term surveillance.

Pre-transplant histology does not improve prediction of 5-year kidney allograft outcomes above and beyond clinical parameters.

Pre-implant kidney biopsy is used to determine suitability of marginal donor kidneys for transplantation. However, there is limited data examining the utility of pre-implant histology in predicting medium term graft outcome. This retrospective study examined kidney transplants over a 10-year period at a single center to determine if pre-implant histology can identify cases of eGFR ≤35 ml/min/1.73m2 at 5 year follow up beyond a clinical predictive logistic regression model. We also compared outcomes of dual kidney transplants with standard single kidney transplants. Of 1195 transplants, 171 received a pre-implant kidney biopsy and 15 were dual transplants. There was no significant difference in graft and patient survival rates. Median eGFR was lower in recipients of biopsied kidneys compared with standard kidney transplants (44 vs. 54 ml/min/1.73m2, p < .001). Median eGFR of dual transplant and standard kidney transplants were similar (58 vs. 54 ml/min/1.73m2, p = .64). Glomerular sclerosis (p = .05) and Karpinski Score (p = .03) were significant predictors of eGFR at 5-years in multivariate analysis but did not improve discrimination of eGFR ≤35 ml/min/1.73m2 at 5-years beyond a clinical prediction model comprising donor age, donor hypertension and terminal donor creatinine (C-statistic 0.67 vs. 0.66; p = .647). Pre-implant histology did not improve prediction of medium-term graft outcomes beyond clinical predictors alone. Allograft function of dual transplant kidneys was similar to standard transplants, suggesting that there is scope to increase utilization of kidneys considered marginal based on histology.

A novel approach to improve undergraduate surgical teaching.

BACKGROUND: Undergraduate surgery is at an important crossroads. Many departments report significant difficulties delivering effective teaching. Our student feedback indicated a dated surgical curriculum lacking structure, quality and uniformity. We report on a new "blended" approach employing a combination of professional DVDs, case based discussions, online material and traditional bedside teaching designed to provide structure, standardization, and equality of learning . METHODS: Year 4 students who had undertaken the new course and year 5 students who had participated in the traditional teaching programme were compared. Students completed a 20 item questionnaire about their experiences of the surgical teaching programme. RESULTS: One hundred and seventy-one year 4 (70%) and 148 year 5 students (66%) responded. Domains relating to "Overall Satisfaction with the course", "Approval of innovative teaching methods and interactivity" and "Satisfaction with the clarity of course information" showed improvements when comparing the new and old programmes. However bedside teaching was not rated as highly in the new programme (p<0.05). CONCLUSION: This blended approach has resulted in improved student understanding and engagement. The apparent compromise of bedside teaching may be a reflection of higher expectations. We believe that a similar blended approach has the potential to re-invigorate surgical teaching elsewhere.

Bilateral renal cortical necrosis in meningococcal meningitis.

Bacterial meningitis is a relatively common infection of the cerebrospinal fluid (CSF) and leptomeninges. The clinical picture evolves rapidly and, if treatment is delayed, can result in a variety of long-term sequelae, including death. Acute kidney injury in the setting of bacterial meningitis usually results from hypotension and volume depletion and resolves with appropriate treatment. Meningococcaemia with profound hypotension, and/or disseminated intravascular coagulopathy (DIC) may very rarely lead to bilateral renal cortical necrosis. In this context, renal recovery is extremely unlikely. We present two cases of meningococcaemia complicated by bilateral renal cortical necrosis and, ultimately, end stage kidney disease. We also present a review of the literature on the subject. The cases outline the importance of early aggressive intervention by a multidisciplinary team.

Relapsing tubulointerstitial nephritis in an adolescent with inflammatory bowel disease without aminosalicylate exposure.

A 14-year-old boy presented with ongoing constipation as a manifestation of newly diagnosed Crohn's disease (CD) and a concomitant decline in renal function with biopsy-proven interstitial nephritis. Initiation of steroid therapy and mesalazine was associated with an improvement in symptoms and renal function. We describe a rare case of a 5-aminosalicylic acid (5-ASA)-naïve patient who developed interstitial nephritis in association with CD with no evidence of other primary glomerulopathy. A unique feature of the case being a profound systemic inflammatory response at the time of diagnosis and a relapse in nephritis 2 months after cessation of mesalazine in the absence of any macroscopic colitis.

Trimethoprim-sulfamethoxazole induced acute interstitial nephritis in renal allografts; clinical course and outcome.

BACKGROUND: Acute interstitial nephritis (AIN) secondary to trimethoprim-sulfamethoxazole (TMP-SMX) is well documented as a cause of acute renal failure in native kidneys. TMP-SMX is the standard prophylactic agent against pneumocystis carinii (PCP) used in the early post-transplant period, however, it has to date only been indirectly associated with AIN in renal allografts. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We describe eleven renal transplant patients with acute allograft dysfunction in whom a transplant biopsy demonstrated primary histopathologic features of allergic AIN, all of whom were receiving TMP-SMX in addition to other medications known to cause AIN. RESULTS: All cases occurred within 1 month of transplantation and accounted for 2.12% (11/518) of the total number of transplant biopsies performed during the study period. However, this figure increased to 10.1% (11/109) when those biopsies performed for early allograft dysfunction (< 1 month) were taken into account. After discontinuation of TMP- SMX alone, all patients had an immediate improvement in serum creatinine with excellent long term allograft function - mean improvement of serum creatinine from 465 micromol/l to 136 micromol/l at last follow-up (range 15 - 55 months). CONCLUSIONS: AIN secondary to TMP-SMX, although an uncommon cause of allograft dysfunction over the study period, accounted for over 10% of cases of allograft dysfunction within the first month of transplantation. Therefore, a high degree of clinical suspicion for TMP-SMX-induced AIN is warranted when confronted with early acute allograft dysfunction.

Higher tacrolimus trough levels on days 2-5 post-renal transplant are associated with reduced rates of acute rejection.

We analyzed the association between whole-blood trough tacrolimus (TAC) levels in the first days post-kidney transplant and acute cellular rejection (ACR) rates. Four hundred and sixty-four consecutive, deceased-donor kidney transplant recipients were included. All were treated with a combination of TAC, mycophenolate mofetil and prednisolone. Patients were analyzed in four groups based on quartiles of the mean TAC on days 2 and 5 post-transplant: Group 1: median TAC 11 ng/mL (n = 122, range 2-13.5 ng/mL), Group 2: median 17 ng/mL (n = 123, range 14-20 ng/mL), Group 3: median 24 ng/mL (n = 108, range 20.5-27 ng/mL) and Group 4: median 33.5 ng/mL (n = 116, range 27.5-77.5 ng/mL). A graded reduction in the rates of ACR was observed for each incremental days 2-5 TAC. The one-yr ACR rate was 24.03% (95% CI 17.26-32.88), 22.20% (95% CI 15.78-30.70), 13.41% (95% CI 8.15-21.63) and 8.69% (95% CI 4.77-15.55) for Groups 1-4, respectively (p = 0.003). This study suggests that higher early TACs are associated with reduced rates of ACR at one yr.

Mycobacterium tuberculosis in a renal transplant transmitted from the donor.

BACKGROUND: Disease caused by Mycobacterium tuberculosis (MTB) is a well-recognised complication of renal transplantation worldwide due to immunosuppression. It is more common in developing countries. Infection isolated to a renal allograft is rare and infection transmitted by the allograft is also very rare. AIM: To describe the first reported case of MTB in a renal transplant transmitted from the donor in Ireland and review the literature. RESULTS: A 53-year-old male 29 months after allogenic renal transplant for adult polycystic kidney disease with no other risk factors for MTB presented with deteriorating renal function. Pathological examination of a renal biopsy specimen showed caseating granulomata. MTB was confirmed by culture of early morning urine. CONCLUSIONS: MTB isolated to a renal transplant is rare in the developed world. Such an infection should always be considered as our donor pool becomes increasingly more travelled particularly to endemic areas. The new interferon gamma release assays (IGRA) may be a viable alternative screening method to the tuberculin skin test (TST).

AA amyloidosis in psoriatic arthritis.

BACKGROUND: Amyloidosis is an extremely rare complication of psoriatic arthritis (PsA) and is associated with a poor prognosis. We report a case of amyloidosis secondary to severe PsA in a young patient and the course of his disease over a 13-year period of aggressive immunosuppression. METHODS: Diagnosis of renal amyloidosis was made on biopsy: multi-agent immunosuppressive therapy was continued with stabilisation of renal function. RESULTS: Marked deterioration in renal function subsequently occurred following a reduction in cyclosporin A (CyA) dose and repeat biopsy confirmed worsening amyloidosis. CONCLUSION: This case report emphasises the need for aggressive control of the inflammatory response in secondary amyloidosis.

Severity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk.

Previous studies suggested that membranoproliferative glomerulonephritis (MPGN) type II has a worse renal survival and an unacceptable risk of recurrence post transplantation. We hypothesised that other factors may determine this risk. We analysed all cases (n=70) of MPGN diagnosed by renal biopsy in Ireland from 1972 to 1995. We used Cox regression analysis to determine factors that were independently predictive of renal failure. MPGN II had more crescent formation and mesangial proliferation (P<0.05). Mean follow-up duration was 13.8 years, during which time 41 (58.6%) developed end-stage renal failure (ESRF). The median time to ESRF was 8.3 years (95% confidence interval 5.7-10.9) and 5-, 10-, and 20-year probabilities of ESRF were 32, 54, and 70%, respectively. Multivariate analysis revealed that severity of interstitial fibrosis (P<0.05), crescent formation (P<0. 01) and mesangial proliferation (P<0.05) were independently associated with ESRF. Decade of diagnosis, age, MPGN type, and creatinine or complement level at baseline did not predict renal survival in this model. In 21 (49%) of the 43 renal transplants, MPGN recurred. Younger age at initial diagnosis (P<0.01) and the presence of crescents on the original biopsy (P<0.005) were independently associated with recurrence on multivariate analysis. MPGN type was not associated with recurrence in this model. Contrary to previous reports, after controlling for crescent formation, MPGN II was not associated with more ESRF or recurrence in the allograft. It is therefore the more aggressive glomerular changes associated with MPGN II, rather than the disease type per se, that determine outcome.

Renal transplantation in the elderly--the Irish experience.

BACKGROUND: The aim of this paper was to evaluate patient and kidney graft survival rates in renal transplant recipients and compare the outcomes between the different patient age groups. METHODS: A retrospective review of all adult renal transplants performed at Beaumont Hospital between the years 1986-2001 was carried out. Patients were defined as 'elderly' if they were 65 years of age or older and 'younger' if less than 65 years at the time of transplantation. Patient and transplant graft survival rates were analysed for each age group. RESULTS: Data were analysed on 1462 'younger' patients and 105 'elderly' renal transplant recipients. Estimated patient survival at 1, 5 and 10 years were 96%, 87% and 74% in the younger patient group compared to 85%, 59% and 33% in the elderly group. The adjusted graft survival rates (adjusted for death due to other causes and with a functioning graft in situ) for the younger group were 89%, 77% and 64% at one, five and ten years respectively, while for the elderly group, adjusted one, five and ten year survival rates were 89%, 83% and 70% respectively. CONCLUSIONS: Although the elderly have a shorter life expectancy than the younger population they do benefit from renal transplantation similar to the younger recipients.

DNA array analysis in a Microsoft Windows environment.

Microsoft Windows-based computers have evolved to the point that they provide sufficient computational and visualization power for robust analysis of DNA array data. In fact, smaller laboratories might prefer to carry out some or all of their analyses and visualization in a Windows environment, rather than alternative platforms such as UNIX. We have developed a series of manually executed macros written in Visual Basic for Microsoft Excel spreadsheets, that allows for rapid and comprehensive gene expression data analysis. The first macro assigns gene names to spots on the DNA array and normalizes individual hybridizations by expressing the signal intensity for each gene as a percentage of the sum of all gene intensities. The second macro streamlines statistical consideration of the confidence in individual gene measurements for sets of experimental replicates by calculating probability values with the Student's t test. The third macro introduces a threshold value, calculates expression ratios between experimental conditions, and calculates the standard deviation of the mean of the log ratio values. Selected columns of data are copied by a fourth macro to create a processed data set suitable for entry into a Microsoft Access database. An Access database structure is described that allows simple queries across multiple experiments and export of data into third-party data visualization software packages. These analysis tools can be used in their present form by others working with commercial E. coli membrane arrays, or they may be adapted for use with other systems. The Excel spreadsheets with embedded Visual Basic macros and detailed instructions for their use are available at http://www.ou.edu/microarray.

Myocardial expression of the endothelin system in endotoxin-treated rats.

Although circulating plasma levels of endothelin (ET)-1 are elevated in endotoxemia, little is known about the myocardial expression of the ET system in endotoxic shock. We assessed the temporal mRNA expression pattern of key components of the ET system (pre-pro ET (ppET) -1, -2, ET-converting enzyme-1, ET(A) and ET(B) receptors) by reverse transcription polymerase chain reaction in a rat model of early endotoxic shock. Lipopolysaccharide (5 mg/kg, i.p.) caused a transient increase (p < 0.05) in inducible nitric oxide synthase mRNA expression. ppET-1 mRNA expression was increased at 2 h (approximately 12-fold increase; p < 0.05) in the lipopolysaccharide compared with the saline group and ppET-2 mRNA expression was unaltered. ET-converting enzyme-1, ET(A), and ET(B) receptor mRNA expression was unaltered in the lipopolysaccharide compared with the saline group. While ppET-1 mRNA expression is selectively upregulated in ventricular myocardium of lipopolysaccharide-treated rats, an absence of alteration in ET-converting enzyme-1 mRNA expression suggests an excess capacity of ET-converting enzyme-1 to cope with the increased expression of ET-1. At the level of the receptor, endotoxic shock did not affect the expression of either ET(A) or ET(B) receptor mRNA. These data are consistent with the increased expression of myocardial ET-1 as an acute-phase response due to hemodynamic instability associated with the early stages of endotoxic shock.

Successful transplantation of kidneys from a donor with HELLP syndrome-related death.

We report on the successful use of kidneys procured from a donor with HELLP syndrome. The use of organs from a donor with HELLP syndrome has not been reported previously, perhaps because of the renal complications associated with it. Both recipients have been doing well since renal transplantation, with immediate graft function and acceptable graft function at 2 years of follow-up. In view of the continuing shortage of cadaveric kidneys for transplantation, this report highlights how organs from "marginal" donors should not be discarded without worthy consideration.

Mesangioproliferative glomerulonephritis with IgM deposition: clinical characteristics and outcome.

The significance of IgM on immunofluorescence in renal biopsy specimens remains unclear. This retrospective case study was conducted to define the clinical features, response to therapy and outcome of patients with Mesangioproliferative Glomerulonephritis (MGN) with diffuse IgM deposition. Of 1919 native renal biopsies performed over a ten-year period, 139 (7.2%) had light microscopic features of MGN and manifested IgM as the dominant immunoglobulin. When exclusion criteria (more than a trace of IgA or IgG, segmental IgM, evidence of SLE, vasculitis, FSGS or Alport's syndrome and pregnant patients) were applied, 60 patients (3.1%) remained. Follow-up data were available for 54 cases with a mean age of 26.5 years (range 1.7-63). Mean follow-up period was 7.4 years (range 4.7-22.2). Forty-one per cent presented with nephrotic syndrome (NS), 26% with asymptomatic proteinuria (>250mg/24hr), 18% with macroscopic hematuria and 15% with isolated microscopic hematuria. Twenty-one percent of patients were hypertensive at presentation. Creatinine was initially <120 (mol/L in all but one patient. Only four patients (7.4%), all nephrotic, suffered a decline in renal function despite treatment; all 4 developed ESRF after a mean of 5.6 years (range 2-8.3). Two of these were subsequently re-biopsied and found to have FSGS. No patients with isolated microscopic / macroscopic hematuria or asymptomatic proteinuria suffered a decline in renal function. Protein excretion rate fell into the normal range in 63% of those receiving steroids, with 82% becoming steroid dependent. Of those treated with cyclosporine (48%) or cyclophosphamide (52%) only 9.5% and 14.5% respectively remained in prolonged remission after discontinuing treatment. It is concluded that MGN with IgM deposition carries a very favorable prognosis except in patients with NS who develop FSGS. However there is a high incidence of steroid dependence and resistance in the proteinuric group.

Hemolytic-uremic syndrome in association with both cyclosporine and tacrolimus.

Hemolytic-uremic syndrome (HUS) is a well-recognized complication of cyclosporine (CyA) therapy. Transplant recipients with this complication are frequently switched to tacrolimus, although this drug has also been implicated. We report a case of a renal transplant recipient who developed severe graft dysfunction due to biopsy-proven HUS after receiving CyA. Renal function and hemolytic parameters improved with discontinuation of the drug, but they deteriorated again after commencement of tacrolimus 15 days later. A second transplant biopsy demonstrated fresh lesions diagnostic of HUS. Hemolytic parameters resolved with discontinuation of tacrolimus. This is the first report of metachronous HUS being caused in a renal transplant by both CyA and tacrolimus. We therefore believe that caution should be exercised when using tacrolimus as rescue therapy in patients with CyA-induced HUS.

Two novel human RAB genes with near identical sequence each map to a telomere-associated region: the subtelomeric region of 22q13.3 and the ancestral telomere band 2q13.

Two closely related genes have been identified at 2q13 and 22q13.3. These genes show similarity to members of the RAB family of small GTPases. RABL2A and RABL2B differ by three conservative amino acid changes over a total of 228 residues. Both are expressed in all tissues tested. Northern analysis showed that a 2.5-kb transcript is expressed in all tissues tested while a 1.4-kb transcript is specifically expressed only in muscle. The size difference between these two transcripts is the result of differential splicing of an intron within the 3' UTR. RABL2B is located within the subtelomeric region of 22q13.3. RABL2A maps to 2q13, the site of an ancestral telomere fusion event, suggesting that it also may be a subtelomeric gene.

Substance abuse in an Irish antenatal population.

Substance abuse is prevalent in Ireland. The potential sequelae for abuser and carer are many. In pregnancy there are further problems. We assessed the prevalence of substance abuse in our antenatal population using an anonymous questionnaire and urine toxicology screening. We examined 522 women and 18 (3.4%) had positive urine toxicology. The anonymous questionnaire failed to identify all of these women. No typical patient profile emerged when the demographic features were studied. We believe that our study has underestimated the true prevalence of substance abuse in our antenatal population and many factors may have contributed to this. Substance abuse in pregnancy remains a difficult problem to quantify and for the future the main focus of attention must be on education and prevention.